The objective of this research is to elucidate the mechanism of action of insecticides on the nerve membrane which is the most critical target site of a variety of insecticides. Sophisticated electrophysiological techniques developed in our laboratory for the study of insecticides will be fully utilized, including intracellular microelectrode, voltage clamp, intracellular perfusion, and fluctuation analysis. The insecticides used for this study are DDT and its analogs and derivatives, and a variety of synthetics pyrethroids. The proposed study may be divided into three large categories. One is the detailed ionic mechanism of action of insecticides on the nerve membrane ionic channels. Kinetic analyses will be performed using Hodgkin-Huxley formulation and the role of membrane surface charges and dipole potential in the toxic actions of insecticides will be explored. Fluctuation analyses will also be carried out in order to study the interaction of insecticides with individual ionic channels of nerve membranes. The second project is concerned with the mechanism of action of insecticides on synaptic transmission. The interaction of insecticides with the pre- and postsynaptic elements will be analyzed in detail. The third project involves the establishment of the true structure-activity relationship of insecticides by comparison of the direct action on the nerve (target site) as a measure of activity. Some of these analogs, derivatives and isomers are selected for voltage clamp analyses to interpret the structure-activity relationship in terms of membrane ionic conductances. These studies will provide the basis for the molecular mechanism of action of insecticides and clues to improvement of the existing insecticides.